The molecular mechanisms underlying pathogenesis in the majority of sporadic Alzheimer's disease (SAD) cases are largely unknown; complex interactions between multiple environmental factors, such as diet and life style, along with genetic factors are all significant contributors. Classic cardio-metabolic risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia have also been shown to increase the risk of SAD with several common features, including insulin resistance, neuroinflammation and endothelial dysfunction. Our pilot study indicates that combination of a typical Western diet (TWD) with physiologically relevant high cholesterol content with mice deficient in vascular nitric oxide synthase gene (eNOS) induces significant AD-like phenotypes including increased amyloidogenesis, metabolic changes and neuroinflammation. We hypothesize that by combining the global vascular risk factor with long-term TWD (>8 months), we will create a representative non-transgenic mouse model for SAD in middle-aged non-transgenic C57BL/6 mice. To test this hypothesis, two specific aims are proposed accordingly to 1) determine the effects of a TWD in eNOS-deficient mice (eNOS-/- and eNOS+/-) on AD-related cognitive measures by various behavioral tests and 2) to comprehensively characterize AD-like phenotypes in the selected diet model. Given our success, the model will provide a useful tool to unravel further mechanistic associations between cardiovascular diseases, diabetes and AD. Validation of a number of identified diabetic genes as AD risk genes will encourage us to use this model in the future to conduct a genome- wide gene analysis to identify new vascular-metabolic risk genes for AD.